A Dose Escalation Phase I Study to Assess the Safety and Clinical Activity of Multiple Cancer Indications

NCT ID: NCT03018405

Last Updated: 2019-09-19

Basic Information

• Recruitment Status: UNKNOWN
• Clinical Phase: PHASE1/PHASE2
• Total Enrollment: 146 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2016-12-31
• Study Completion Date: 2021-08-31

Brief Summary

THINK (THerapeutic Immunotherapy with NKR-2) is a multinational (EU/US) open-label Phase I study to assess the safety and clinical activity of multiple administrations of autologous NKR-2 cells in seven refractory cancers, including five solid tumors (colorectal, ovarian, bladder, triple-negative breast and pancreatic cancers) and two hematological tumors (acute myeloid leukemia and multiple myeloma).

Detailed Description

This open-label Phase I study aims at assessing the safety and clinical activity of the NKR-2 treatment administered 3 times with a 2-week interval between each administration in different tumor types. In absence of progressive disease at the first tumor assessment following NKR-2 administratio, the patient will receive a new cycle of 3 administrations maximum with a 2-week interval. The study will contain two consecutive segments: a Phase I dose escalation and a Phase I expansion segment.

The Phase I dose escalation segment will include 2 arms, one in solid tumors and one in hematological tumors. The dose escalation design will include 3 dose levels: The dose escalation phase will consist of 3 cohorts (Cohorts 1-3) for the solid tumors, and 3 cohorts (Cohorts 4-6) for the hematological tumors; with each set of 3 cohorts receiving escalating doses of the NKR-2 therapy.

Two additional cohorts will be added in each dose escalation arm with the aim to provide a more intense treatment during the induction treatment. These additional cohorts in both the solid arm (cohort 8-9 - only in CRC) and in the hematological arm of the study (cohort 10-11 - only in AML/MDS) will therefore evaluate a tighter schedule of NKR-2 injections with the three first injections within the induction cycle separated by a 1-week interval followed two weeks later by a second cycle (cycle 2) with a 2-weeks interval between each three NKR 2 injections. These cohorts will each enroll 3 patients in case of no DLT. Based on safety and early clinical data from these cohorts, the specific schedule of cohorts 8-11 might be selected for the expansion.

Conditions

Acute Myeloid Leukemia/Myelodysplastic Syndrome; Multiple Myeloma (MM)

Study Design

• Allocation Method: NON_RANDOMIZED
• Intervention Model: SINGLE_GROUP
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

Hematological tumors

The dose escalation arm for hematological tumors will use a 3 +3 design to determine the maximum tolerated dose. Two additional cohorts will be added in this dose escalation arm with the aim to provide a more intense treatment during the induction treatment (cycle 1 of injection). Cohort 10-11 (only in AML/MDS) will evaluate a tighter schedule of NKR-2 injections at 1x109 or potentially 3x109 NKR-2 per injection with the three first injections within the induction cycle (cycle 1) separated by a 1-week interval followed two weeks later by a second cycle (cycle 2) with a 2-weeks interval between each three NKR 2 injections.

Group Type: EXPERIMENTAL

NKR-2 cells

Intervention Type: BIOLOGICAL

In cohorts 1-6, the schedule of administration will be 3 NKR-2 doses administered with a 2-week interval. In absence of progressive disease at the first tumor assessment following NKR-2 administration (on Visit D29 for hematological tumors or on Visit D57 for solid tumors), and according to product availability, the patient will receive a new cycle of 3 administrations maximum with a 2-week interval, at a dose of 1x109 NKR-2 cells per injection, or at the same dose of cycle 1 if it was below 1x109 NKR-2 cells.

Patients in cohorts 8-9 (solid arm) and 10-11 (hematological arm) of first segment will receive 3 treatment doses at 1x109 NKR-2 (cohorts 8 and 10) or 3x109 NKR-2 (cohorts 9 and 11) per injection, with a 1-week interval between each dose. A second cycle of three NKR-2 injections at the same dose as in 1st cycle will be administered 2 weeks after the third NKR-2 injection, and with a 2-week interval between each dose.

Solid Tumors

The dose escalation arm for solid tumors will use a 3 +3 design to determine the maximum tolerated dose. Two additional cohorts will be added in this dose escalation arm with the aim to provide a more intense treatment during the induction treatment (cycle 1 of injection). Cohort cohort 8-9 ( only in CRC) will evaluate a tighter schedule of NKR-2 injections at 1x109 or potentially 3x109 NKR-2 per injection with the three first injections within the induction cycle (cycle 1) separated by a 1-week interval followed two weeks later by a second cycle (cycle 2) with a 2-weeks interval between each three NKR 2 injections.

Group Type: EXPERIMENTAL

NKR-2 cells

Intervention Type: BIOLOGICAL

In cohorts 1-6, the schedule of administration will be 3 NKR-2 doses administered with a 2-week interval. In absence of progressive disease at the first tumor assessment following NKR-2 administration (on Visit D29 for hematological tumors or on Visit D57 for solid tumors), and according to product availability, the patient will receive a new cycle of 3 administrations maximum with a 2-week interval, at a dose of 1x109 NKR-2 cells per injection, or at the same dose of cycle 1 if it was below 1x109 NKR-2 cells.

Patients in cohorts 8-9 (solid arm) and 10-11 (hematological arm) of first segment will receive 3 treatment doses at 1x109 NKR-2 (cohorts 8 and 10) or 3x109 NKR-2 (cohorts 9 and 11) per injection, with a 1-week interval between each dose. A second cycle of three NKR-2 injections at the same dose as in 1st cycle will be administered 2 weeks after the third NKR-2 injection, and with a 2-week interval between each dose.

Interventions

NKR-2 cells

In cohorts 1-6, the schedule of administration will be 3 NKR-2 doses administered with a 2-week interval. In absence of progressive disease at the first tumor assessment following NKR-2 administration (on Visit D29 for hematological tumors or on Visit D57 for solid tumors), and according to product availability, the patient will receive a new cycle of 3 administrations maximum with a 2-week interval, at a dose of 1x109 NKR-2 cells per injection, or at the same dose of cycle 1 if it was below 1x109 NKR-2 cells.

Patients in cohorts 8-9 (solid arm) and 10-11 (hematological arm) of first segment will receive 3 treatment doses at 1x109 NKR-2 (cohorts 8 and 10) or 3x109 NKR-2 (cohorts 9 and 11) per injection, with a 1-week interval between each dose. A second cycle of three NKR-2 injections at the same dose as in 1st cycle will be administered 2 weeks after the third NKR-2 injection, and with a 2-week interval between each dose.

Intervention Type: BIOLOGICAL

Other Intervention Names

NKG2D-CAR construct

Eligibility Criteria

Inclusion Criteria

• Men or women ≥ 18 years old at the time of signing the ICF,
• Patient with a CRC, epithelial ovarian cell or fallopian tube carcinoma, urothelial carcinoma, TNBC, pancreatic cancer, AML/MDS or MM,
• Disease must be measurable according to the corresponding guidelines,
• Patient with an ECOG performance status 0 or 1, and AML patients with anemia resulting in an ECOG performance status of 2,
• Patient with adequate bone marrow reserve, hepatic and renal functions.
• Patients must have sufficient pulmonary functions with a Forced Expiratory Volume in the first second (FEV-1)/Forced Vital Capacity (FVC) ≥ 0.7 with FEV-1 ≥ 50% predicted.

Exclusion Criteria

• Patient with a tumor metastasis in the central nervous system,
• Patients who have received another cancer therapy within 2 weeks before the planned day for the apheresis (except hydroxyurea for AML patients),
• Patients who receive or are planned to receive any other investigational product within the 3 weeks before the planned day for the first NKR-2 administration (except hydroxyurea for AML patients),
• Patient is under systemic immunosuppressive drugs, unless specific cases authorized per protocol,
• Patients who have received other cell therapies,
• Patients who underwent major surgery within 4 weeks before the planned day for the first NKR-2 administration.
• Patient cannot present with history of idiopathic pulmonary fibrosis, organizing pneumonia, drug-induced pneumonitis, idiopathic pneumonitis and/or active or acute exacerbation of chronic obstructive pulmonary disease (COPD).

Detailed disease specific criteria exist and can be discussed with contacts listed below.

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Celyad Oncology SA

INDUSTRY

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Frédéric Lehmann, MD

Role: PRINCIPAL_INVESTIGATOR

Celyad Oncology SA

Locations

Tampa, Florida, United States

Site Status: RECRUITING

Buffalo, New York, United States

Site Status: RECRUITING

Brussels, , Belgium

Site Status: RECRUITING

Brussels, , Belgium

Site Status: RECRUITING

Ghent, , Belgium

Site Status: RECRUITING

Countries

United States; Belgium

Central Contacts

Amélie Vanneste

Role: CONTACT

avanneste@celyad.com

Anne Flament, MD

Role: CONTACT

aflament@celyad.com

Facility Contacts

Jeff Edelman

Role: primary

Jeffrey.Edelman@moffitt.org

813-745-1040

Amy Whitworth

Role: primary

ASKRPCI@roswellpark.org

877-275-7724

Anne Moxhon

Role: primary

anne.moxhon@uclouvain.be

+32 2 764.42.17

Michel Dubuisson

Role: primary

michel.dubuisson@bordet.be

+32 (0) 2 541 31 79

Jonas Segaert

Role: primary

jonas.segaert@uzgent.be

32 (0)9 332 4912

Liesbeth Delanghe

Role: backup

Liesbeth.delanghe@uzgent.be

References

Sallman DA, Kerre T, Havelange V, Poire X, Lewalle P, Wang ES, Brayer JB, Davila ML, Moors I, Machiels JP, Awada A, Alcantar-Orozco EM, Borissova R, Braun N, Dheur MS, Gilham DE, Lonez C, Lehmann FF, Flament A. CYAD-01, an autologous NKG2D-based CAR T-cell therapy, in relapsed or refractory acute myeloid leukaemia and myelodysplastic syndromes or multiple myeloma (THINK): haematological cohorts of the dose escalation segment of a phase 1 trial. Lancet Haematol. 2023 Mar;10(3):e191-e202. doi: 10.1016/S2352-3026(22)00378-7. Epub 2023 Feb 7.

Reference Type: DERIVED

PMID: 36764323 (View on PubMed)

Lonez C, Verma B, Hendlisz A, Aftimos P, Awada A, Van Den Neste E, Catala G, Machiels JH, Piette F, Brayer JB, Sallman DA, Kerre T, Odunsi K, Davila ML, Gilham DE, Lehmann FF. Study protocol for THINK: a multinational open-label phase I study to assess the safety and clinical activity of multiple administrations of NKR-2 in patients with different metastatic tumour types. BMJ Open. 2017 Nov 12;7(11):e017075. doi: 10.1136/bmjopen-2017-017075.

Reference Type: DERIVED

PMID: 29133316 (View on PubMed)

Other Identifiers

CYAD-N2T-002

Identifier Type: -

Identifier Source: org_study_id